Sepsis

Reuben Ramphal M.D.

Division of Infectious Diseases
University Of Florida

October 31, 2005 11:00
Occurrence of Severe Sepsis
Annual incidence: ~750,000 cases in US

2.26 cases per 100 hospital discharges
51.1% received ICU care and 17.3% received IMC care
Incidence and mortality increased with age
Case fatality rate: 28%
Economic burden
$22,100 per case
~$16.7 billion nationally
Angus DC et al. 2001. Crit Care Med 29:1303-1310.

Reference Diseases
Incidence in US (cases per 100,000)
AIDS
1
17
Colon and rectal cancer
2
48
Breast cancer
2
112
Congestive heart failure
3
~196
Severe sepsis
4
~300
Number of deaths in US each year
Acute myocardial infarction
5
218,000
Severe sepsis
4
215,000

1
Centers for Disease Control and Prevention. 2000. Incidence rate for 1999.
2
American Cancer Society. 2001. Incidence rate for 1993-1997.
4
Angus DC et al. 2001. Crit Care Med 29:1303-1310.
5
National Center for Health Statistics. 2001.




Sepsis on the Rise
Incidence projected to rise to 1.0 million
cases annually in US during the next decade
Aging population
Increased awareness and diagnosis
Immunocompromised patients
Invasive procedures
Resistant pathogens


Angus DC et al. 2001. Crit Care Med 29:1303-1310.
Balk RA. 2000. Crit Care Clin 16(2):179-191

Definitions
SIRS Sepsis
Severe
Sepsis
Septic
Shock
Infection
Systemic Inflammatory
Response Syndrome
Systemic Inflammatory Response
Syndrome (SIRS)
2 of the following:
Temp > 38C or < 36C
Heart rate > 90 bpm
Respiratory rate > 20 bpm
WBC > 12,000, < 4,000 or bands > 10%
Bone, et al. 1992. Chest 101:1644-1655
Sepsis
Sepsis
SIRS + infection
Severe sepsis
Sepsis with organ dysfunction, hypoperfusion or
hypotension
Septic Shock
Sepsis with hypotension and perfusion
abnormalities despite adequate volume
replacement
Bone, et al. 1992. Chest 101:1644-1655
Mortality from Sepsis Martin NEJM 2003
Changes in the Causes of Sepsis
Martin NEJM 2003
Pathogenesis of Sepsis
Interaction of specific Pathogen associated
molecular patterns (PAMPs--microbial
ligands) on organisms with specific receptors
Toll like receptors (Tlrs) on animal cells
PAMPs
Highly conserved parts of microbial molecules
Sepsis also caused by Interactions of super
antigens with T- cells e.g. Some
staphylococcal and streptococcal toxins
Innate Immune response Sepsis
Interaction of a PAMP with a Tlr results in a
cellular cascade which leads to activation of
innate immune mechanisms
Message sent to nucleus resulting in transcription
of repressed genes
Antimicrobial peptide synthesis and release
Beginning of a specific adaptive antibody
response
Release of Mediators of inflammation
Normally protective but some type of
dysregulation leads to signs of SEPSIS
Akira and Hashino, Osaka University JID 2003
Microbial Ligands Recognized by TLR family
Microbial Ligands and Tlr recognition
Synthesis and release of effector molecules
Pathogenesis of Severe Sepsis
Infection
Microbial Products
(exotoxin/endotoxin)
Cellular Responses
Oxidases
Platelet
Activation
Kinins
Complement
Coagulopathy/DIC
Vascular/Organ System Injury
Multi-Organ Failure
Death
Coagulation
Activation
Cytokines
TNF, IL-1, IL-6
Clinical effects of dysregulation of innate
immune responses
Clinical sepsis
Fever
Hypoperfusion
Hypotension Shock
Clotting Disseminated intravascular
coagulation
Renal failure
Cardiac depression
Central nervous system depression
Acute respiratory Distress syndrome
Most effective therapies
Early recognition of preshock- tachynea
leading to respiratory alkalosis
Low Pco
2,
pH >7.45
Lots of Fluids-crystalloid or colloid
Antibiotics
Effective antibiotics
Timely administration of Effective
antibiotics
Effect of antibiotics on Survival from sepsis


Independent risk factors for mortality for 136 patients
with Pseudomonas aeruginosa bacteremia.




Risk factor OR (95% CI) P

Ineffective definitive antibiotic treatment 11.68 (2.5154.38) .002
Ineffective empirical antibiotic treatment 4.61 (1.1818.09) .028
Presentation with septic shock 45.37 (10.19201.93) <.001
Pneumonia 11.43 (2.6050.19) .001
Increasing APACHE II score 1.31 (1.151.50) <.001

NOTE. Multivariate analysis using logistic regression model.
a Per 1 point increase in score.
Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and
Influence of Delayed Receipt of Effective Antimicrobial Therapy on Clinical Outcome
Cheol-In Kang et al Clin Inf. Dis Oct 03
Timing of Antibiotic administration and mortality
Due Sepsis
What constitutes adequate antibiotic
therapy in Sepsis
Site of Infection if known helps to limit choices
ie-intraabdominal, or necrotizing soft tissue
infection need for anaerobic coverage.
Lung most common site of documented
infection
Resistance picture in hospital if hospital
acquired and in the community if community
acquired
Generally Gram positive and Gram negative
coverage
Baseline Microbiology from a large
Septic shock study
P
e
r
c
e
n
t

o
f

P
a
t
i
e
n
t
s

0
5
10
15
20
25
30
35
Placebo (N=840)
Drotrecogin Alfa
(activated) (N=850)
No
Identifiable
Microorganism
Pure
Fungal
Gram
Mixed
Gram
Negative
Gram
Positive
Primary Sites of Infection in a recent large
study of Septic shock
P
e
r
c
e
n
t

o
f

P
a
t
i
e
n
t
s

0
10
20
30
40
50
60
Placebo N=840
Drotrecogin Alfa
(activated) N=850
Other Skin Blood Urinary
Tract
Intra-
Abdominal
Lung
Site of Infection
Antibiotic Choices
Given the world wide resistance issues
the most effective antibiotic choices to
cover gram negatives would be
Fourth generation cephalosporins
aminoglycoside
Carbapenems aminoglycoside
Pip-Tazobactam + an aminoglycoside
If the incidence of MRSA is high add an
anti Staphylococcal agent --Vanco,
Teicoplanin
Effector mechanism based non antibiotic adjuncts to therapy
IL-1
TNF
APC
Nonantibiotic therapy of septic shock and sepsis
Statistically Significant
Agent Reduction in Mortality
Non steroidal
antiinflammatory drugs

No
Corticosteroids Unresolved
Anti endotoxin No
Anti TNF No
TNF receptor antagonist No
IL-1 receptor antagonist No
PAF antagonist No
Activated protein C Yes


Patients with Adrenal
Insufficiency benefit
from Corticosteroids*
Drotrecogin Alfa (Activated ProteinC)
Reduced 28-Day All-Cause Mortality
0
5
10
15
20
25
30
35
30.8%
24.7%

Placebo
(N=840)
Drotrecogin
Alfa
(activated)
(N=850)
Optimum therapy of sepsis
Antibiotics remain the most critical choice to
be made
TIMELY, EFFECTIVE, BROAD SPECTRUM
Resistance issues need to be kept in mind
Modify antibiotics when organism is known
A large number of patients with the sepsis
syndrome will not have an organism cultured
Agents designed to neutralize the biologic
actions of the inflammatory response may be
additive, but it will likely require multiple
agents